Telomere length and the expression of natural telomeric genes in human fibroblasts: Progressive telomere shortening occurs with division of normal human cells, and eventually leads to replicative senescence. The mechanism by which the shortened telomeres cause growth arrest is largely unknown. Transcriptional silencing of genes adjacent to telomeres, also called telomere position effect, has been hypothesized as a possible mechanism of telomere-mediated senescence. However, there is no report regarding telomere position effect on natural telomeric genes in human cells. To address whether the expression of natural telomeric genes is regulated by telomere length, we combined quantitative RT-PCR with quantitative fluorescence in situ hybridization to comparatively analyze the expression of 34 telomeric genes and telomere length of their 24 corresponding chromosome ends in young and senescent human fibroblasts. We demonstrated here that telomere length alone is not sufficient to determine the expression status of natural telomeric genes. An extended analysis of a tandem of eight telomeric genes on a single chromosome end revealed a discontinuous pattern of changed expression during telomere shortening and some of the changes are senescence specific rather than non-dividing related. This study has led to the identification of a total of eighteen telomeric genes with differential expression in young versus senescent cells. While the function of most of these differentially expressed genes are unknown, CDK10, previously referred to as PISSLRE, has been reported as a member of the CDC2-related kinase that play a role in regulating the G2/M phase of cell cycle, and GAS11 has been implicated in cell growth arrest. Furthermore, it is worth noting that four telomeric genes on the long arm of chromosome 16, where a frequent loss of heterozygosity has been observed in breast cancer, exhibited increased expression in senescent cells. Viewing that replicative senescence is one of the protective mechanisms against tumor formation, it is conceivable that senescence-associated genes may play significant roles in tumor suppression. Further studies will be necessary to elucidate the biological function of the telomeric genes that are differentially expressed in senescent cells.